Table 2.

Principles of a Function-Driven Model of Disorders of Cornification (with Examples)

1.	The Permeability Barrier is abnormal to varying degrees in all ichthyoses. Barrier defects may arise due to:
	a.	Abnormal lipid composition of intercellular membranes leading to lamellar/nonlamellar phase separation
		i.	Inborn errors of lipid metabolism resulting in over- or under- representation of key SC lipids (i.e., cholesterol, free fatty acids, ceramides) that form the lamellar membranes and/or the introduction of other lipid species. (X-Linked I.; NLSD; Refsum disease, ARCI-Lipoxygenase pathway)
		ii.	Failure of lipid processing to key SC lipids due to:
			1.	Deficiency of lipid processing enzymes
				a.	Loss of function mutations (Neonatal Gaucher D.)
				b.	Failure of lamellar body delivery (EHK, CEDNIK Syndrome)
				c.	Proteolytic attack (Netherton)
			2.	Increase in SC pH leading to inhibition of lipid processing enzymes with acidic pH optima (?I. vulgaris)
	b.	Paucity of lamellar membranes due to failure of:
		i.	Lamellar body organellogenesis (Harlequin I.)
		ii.	Lamellar body secretion (EHK; CEDNIK syndrome)
	c.	Abnormal cornified envelope scaffold for organization of lamellar membranes (TGMI-def. ARCI; Loricrin K.)
2.	Homeostatic responses attempt to repair the barrier defect.
	a.	These responses include:
		i.	increased epidermal lipid synthesis
		ii.	epidermal hyperplasia
		iii.	inflammation
	b.	Because of the genetic defect, the barrier defect cannot be repaired and these homeostatic responses are sustained.
	c.	The severity of the barrier defect determines the intensity of the homeostatic repair responses.
	d.	Environmental conditions modify the barrier defect.
		i.	The need for a permeability barrier in the aqueous, in utero environment is much reduced.
		ii.	At birth, the xeric stress of post-natal life augments the barrier repair homeostatic responses. In ichthyoses with severe barrier defects, this stress results in a striking “phenotypic shift” (Harlequin I; EHK; Collodion baby phenotypes).
3. Desquamation is also impaired in all ichthyoses. Abnormal desquamation can be mediated by:
	a.	Delayed or accelerated corneodesmosome proteolysis
		i.	Protease inhibition (X-linked I.) or failure of protease delivery leads to delayed corneodesmosome degradation (Harlequin I; EHK)
		ii.	Loss of protease inhibition leads to accelerated corneodesmosome degradation (Netherton)
	b.	Epidermal hyperplasia with incomplete terminal differentiation
		i.	Entombed lamellar bodies in hyperplastic corneocytes with failure of protease delivery (Hyperplastic ARCI phenotypes)
		ii.	Elevated SC pH inhibiting proteases with acidic pH optima (?I. vulgaris)
	c.	Decreased corneocyte hydration with loss of hydration-related corneocyte swelling exerting mechanical stress on intercellular connections
		i.	Deficiency of filaggrin breakdown products (?I. vulgaris)